Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
Nedd4-family E3 ubiquitin ligases regulate many biological processes including the sodium and iron homeostasis and inflammation. For example, the Nedd4-family members Itch can repress immune function in both innate and adaptive immune cells. Like other Nedd4-family members, Itch normally exists in an auto-inhibited state that prevents their main enzymatic task, transferring ubiquitin to a substrate protein. Thus, to pharmacologically harness Itch activity, one much first determine how auto-inhibition occurs and identify means to “de-repress” its catalytic activity.